More herbicide-tolerant crops, registrations seen

Dill, a panelist at the recent California Weed Science Society conference in San Jose, said his company has six years in the herbicide-tolerant crops marketplace, which has expanded to 125 million acres around the world.

Herbicide-tolerant traits, developed either through regulated biotechnology or time-consuming classical breeding and selection, are appearing in corn, cotton, soybeans, rice, canola, wheat, sugarcane, alfalfa, flowers, and vegetables, and management systems for them have sprung up also.

In the U.S., systems of herbicide-tolerant varieties and companion herbicides have swept into 60 percent of the cotton, 70 percent of the soybeans, 47 percent of the canola, and 25 percent of the corn.

He said canola has peaked and cotton and soybean systems are expected to level off in the next couple of years, but he sees room for growth with systems for corn.

Among the issues of the expanding industry is weed resistance to herbicides. Monsanto’s Roundup, in use for the past 30 years, is no exception. But this does not mitigate the use of the product, said Dill, who is technical portfolio chemistry lead for the company.

Annual ryegrass has shown resistance to glyphosate, Roundup’s active ingredient, in wheat in Australia and in orchards in the U.S., South Africa, and Chile. Mare’s tail also presented a challenge for the product in soybeans and cotton in the U.S.

Management key

"We at Monsanto have found that in these cases management is the key, and we have been very aggressive with a program to solve these problems. In the case of ryegrass, we’ve used pre- and postemergent chemistries, including those of other companies," Dill said.

Mowing to prevent seed formation, mechanical tillage, and crop rotations were also tailored into a management program with the herbicide-tolerant feature at the center.

Monsanto, he said, is also working with universities in the Midwest to examine the possibilities of weed shifts in Roundup Ready corn and soybeans, but none has been found so far.

Some benefit has accrued from growers changing to narrower soybean row configurations that encourage the crop canopy to shade out weeds earlier.

Dill said his company has issued a series of guidelines for growers using herbicide-tolerant cropping systems. The basics: stick to recommended rates, avoid tank-mixes that reduce Roundup efficiency, support rotations of Roundup Ready crops, use Monsanto-developed premix formulations, and report any instances of repeated non-performance.

He expects, he added, to see an increase in current herbicide-tolerant crops, along with expansion, within limits imposed by regulations, of crops directly consumed by humans.

Another panelist, Cliff Gerwick, a herbicide discovery research manager with Dow AgroSciences in Indianapolis, said new herbicides are bound to encounter resistance in weeds, so managing existing herbicide "portfolios" is essential to protect them from future resistance.

"But probably the main reason and the one that is most exciting to me is the innovation in finding new molecular target sites has not stopped with herbicide-tolerant crops."

He said his company is ready for the next generation of tools for weed control, and new molecular target sites, or proteins in weeds that are affected by herbicides, are an important part. Some target sites, but not all, are linked with the "mode of action of the herbicide."

The herbicide industry has about 280 active ingredients and 28 commercial herbicides with unknown modes of action but only 12 molecular target sites.

"Relatively few modes of action make up the bulk of what we spray today, and that is a driver for discovery of new target sites," he said, adding that breakthroughs are increasingly difficult to achieve.

The discovery process can begin with the chemical screening of natural products or traditional herbicides to find a target site.

DNA fingerprinting

Or the process can begin with the target site itself, using DNA technology to find the site and then developing chemistry to affect it. A slight decrease in the level of a protein in a weed may reveal a sensitive target site for a herbicide. Gerwick said he was most excited about prospects of DNA fingerprinting to identify a target site in a plant to see how it reacts to a compound.

Ultimately, he predicted, the discovery of new target sites will depend on an integrated approach using both chemistry and molecular biology, while breakthroughs will occur as a result of the initiative and curiosity of researchers.

Providing a perspective on generic herbicides, often defined as those no longer under patent, was panelist Jim Bone, vice president of product development and governmental affairs for Griffin LLC in Valdosta, Ga.

Bone said discontinuance of a herbicide is most likely due, not to a lack of efficacy, but because it "fails to meet the economic expectations of the registrant."

Those failures are reflected, he said, in the U.S. crop protection chemicals market, which sank by 12 to 15 percent in 2000 and perhaps as much as 25 percent in 2001.

Patents have expired for more than 70 percent of the existing materials, while costs of discovering new products are increasing. At the same time, public sector funding of herbicide research has dropped sharply, and private efforts must bear the costs.

An attraction of generics is the expectation that they cost less than counterpart proprietary products. "You don’t find many generic products staying around that don’t have the ability to bring a return for the investment of the user," Gerwick said.

Inert ingredients

Opportunities for discovery of new products rest with the inert ingredient portion of generics. "It’s possible today to make significant changes to the level of activity of a product based on what you add to enhance or modify the method of delivery." Those include rain-fastness and how the product penetrates the cuticle or other leaf structures.

Aside from improvements or price, he continued, the primary reason for generics remaining on the market is the confidence growers place in them after years of use.

On its pathway to marketing, a generic may be off to a good start after being previously registered and having a source of supply.

"But that’s when the trouble starts," he said. "It must also be substantially similar to the currently registered product. This has become a nightmare-and-a-half for several interesting reasons."

First, the chemical "signature" of the original registration with EPA may not necessarily be the same as the product today because of subtle refinements in production efficiency or other processes of manufacture. The registration is based on the signature of original active ingredient, not what it became years later.

Binding arbitration is often required to determine data compensation the generic marketer owes the original registrant.

The generic marketer may also have to consider revising an original label to reflect current practices that have evolved since the original registration.

Finally, but certainly not least of all, registration by EPA is not sufficient for California’s registration procedure, which takes time.

The generic segment of the crop protection chemicals industry has shifted from what it was a decade ago, he said. It once had little to do with registration and virtually picked up manufacturing and sailed away, so to speak, but today it shoulders the main burden for registration.

"Often we have to carry on extreme regulatory activity which is based less on what is known than what is rumored. Many of us are fighting the battle over alleged endocrine disruption, even after a researcher admitted he falsified data. EPA decided it was a good idea for us to develop some endocrine data, whether the reported data was true or not."

Topping the list for the most-used generic herbicides are glyphosate, paraquat, atrazine, metalachlor, and 2,4-5. Bone named the "top players" as Monsanto, Syngenta, Makhteshim-Agan (Israel), Nufarm (Australia), and Griffin.

He also credited some expansion of the generic segment to herbicide cost reduction gained through mixtures of various products. "As I travel around the United States, I see more people using mixtures to get at specific problems than I’ve seen before. When I ask why, they say they can do it for less than $12 an acre."